The present invention relates to novel pyrazolo[1,5-a]pyrimidine derivatives.
The pyrazolo[1,5-a]pyrimidine derivatives of the invention are novel compounds that have never been described in the literature.
An object of the present invention is to provide compounds useful as medicine.
The present invention provides novel pyrazolo[1,5-a]pyrimidine derivatives represented by the following formula (1) 
wherein
R1 is lower alkyl, phenyl or thienyl;
one of R2 and R3 is hydrogen and the other is naphthyl, furyl, pyridyl, styryl, phenylethynyl, substituted phenyl having 1 to 3 substituents selected from the group consisting of lower alkoxy, phenyl-lower alkoxy and hydroxyl, or phenyl which may have a substituent selected from the group consisting of lower alkylthio, N,N-di-lower alkylamino, halogen-substituted lower alkyl, phenyl, nitro, methylenedioxy and halogen;
R4 is hydrogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxy-carbonyl, lower alkyl, phenylthiomethoxycarbonyl, substituted benzyloxycarbonyl having 1 to 3 substituents selected from the group consisting of lower alkoxy, halogen and nitro, phenoxycarbonyl which may have halogen or nitro as a substituent, carbamoyl, N-lower alkyl-carbamoyl, N-benzylcarbamoyl, N-(lower alkoxy-carbonyl-lower alkyl)carbamoyl, N-(carboxy-lower alkyl)carbamoyl, N-halophenylcarbamoyl, N-(1-lower alkoxy-carbonyl-2-phenylethyl)carbamoyl, N-(1-carboxy-2-phenylethyl)carbamoyl, phenyl which may have halogen as a substituent, or the group 
xe2x80x83wherein R1, R2 and R3 are as defined above.
When R2 is hydrogen, R3 and R4 may conjointly form a group represented by 
wherein the R5s are the same or different and independently represent hydrogen or lower alkoxy.
In the specification, the term xe2x80x9clower alkylxe2x80x9d includes alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
The thienyl group include 2-thienyl and 3-thienyl.
The naphthyl group includes 1-naphthyl and 2-naphthyl.
The furyl group includes 2-furyl and 3-furyl.
The pyridyl group includes 2-pyridyl, 3-pyridyl and 4-pyridyl.
The lower alkoxy group includes alkoxy groups having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like.
The phenyl-lower alkoxy group as a substituent of the substituted phenyl group includes phenyl-substituted alkoxy groups having 1 to 6 carbon atoms, for example, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy and the like.
The substituted phenyl group having 1 to 3 substituents selected from the group consisting of lower alkoxy, phenyl-lower alkoxy and hydroxyl include 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-buthoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,4-dipropoxyphenyl, 3,4-dibutoxyphenyl, 3,4-dipentyloxyphenyl, 3,4-dihexyloxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 3,4,5-triethoxyphenyl, 3,4,5-tripropoxyphenyl, 3,4,5-tributoxyphenyl, 3,4,5-tripentyloxyphenyl, 3,4,5-trihexyloxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-benzyloxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl, 4-(2-phenylethoxy)phenyl, 4-(3-phenylpropoxy)phenyl, 4-(4-phenylbutoxy)phenyl, 4-(5-phenylpentyloxy)phenyl, 4-(6-phenylhexyloxy)phenyl, 4-hydroxy-3-methoxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-hydroxyphenyl, 3-benzyloxy-4-hydroxyphenyl, 3-hydroxy-4,5-dimethoxyphenyl, 4-hydroxy-3,5-dimethoxyphenyl, 3-benzyloxy-4,5-dimethoxyphenyl, 4-benzyloxy-3,5-dimethoxyphenyl, 3,4-dihydroxyphenyl, 3,4-dibenzyloxyphenyl, 3,4,5-trihydroxyphenyl, 3,4,5-tribenzyloxyphenyl and the like.
The lower alkylthio group as a substituent on the phenyl group which may have a substituent selected from the group consisting of lower alkylthio, N,N-di-lower alkylamino, halogen-substituted lower alkyl, phenyl, nitro, methylenedioxy and halogen includes, for example, alkylthio groups having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.
The N,N-di-lower alkylamino group as a substituent on the phenyl group includes, for example, N,N-di-(C1-6-alkyl)amino groups such as N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N,N-dibutylamino, N,N-dipentylamino, N,N-dihexylamino and the like.
The halogen-substituted lower alkyl group as a substituent on the phenyl group includes, for example, perhalogeno-(C1-6-alkyl) groups (wherein halogeno is selected from fluorine, chlorine, bromine and iodine). Specific examples include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonafluorobutyl, undecafluoropentyl, tridecafluorohexyl and the like.
The halogen atom as a substituent on the phenyl group includes fluorine, chlorine, bromine and iodine.
Examples of the phenyl group which may have a substituent selected from the group consisting of lower alkylthio, N,N-di-lower alkylamino, halogen-substituted lower alkyl, phenyl, nitro, methylenedioxy and halogen are unsubstituted phenyl, 2-methylthiophenyl, 3-methylthiophenyl, 4-methylthiophenyl, 4-ethylthiophenyl, 4-propylthiophenyl, 4-butylthiophenyl, 4-pentylthiophenyl, 4-hexylthiophenyl, 2-(N,N-dimethylamino)phenyl, 3-(N,N-dimethylamino)phenyl, 4-(N,N-dimethylamino)phenyl, 4-(N,N-diethylamino)phenyl, 4-(N,N-dipropylamino)phenyl, 4-(N,N-dibutylamino)phenyl, 4-(N,N-dipentylamino)phenyl, 4-(N,N-dihexylamino)phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-heptafluoropropylphenyl, 4-nonafluorobutylphenyl, 4-undecafluoropentylphenyl, 4-tridecafluorohexylphenyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl and the like.
Examples of the lower alkylthio group include those mentioned above as a substituent on the phenyl group.
The lower alkylsulfinyl group includes, for example, (C1-6-alkyl)sulfinyl groups such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl and the like.
The lower alkylsulfonyl group includes, for example, (C1-6-alkyl)sulfonyl groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
The lower alkoxy-carbonyl group includes (C1-6-alkoxy)carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
The substituted benzyloxycarbonyl group having 1 to 3 substituents selected from the group consisting of lower alkoxy, halogen and nitro includes, for example, 2-methoxybenzyloxycarbonyl, 3-methoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3-ethoxybenzyloxycarbonyl, 3-propoxybenzyloxycarbonyl, 3-butoxybenzyloxycarbonyl, 3-pentyloxybenzyloxycarbonyl, 3-hexyloxybenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-iodobenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2,3-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,3-dichlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 3,4-dichlorobenzyloxycarbonyl, 3,5-dichlorobenzyloxycarbonyl, 2,4-dinitrobenzyloxycarbonyl, 3,5-dinitrobenzyloxycarbonyl, 2,3,4-trimethoxybenzyloxycarbonyl, 2,3,5-trimethoxybenzyloxycarbonyl, 2,3,6-trimethoxybenzyloxycarbonyl, 2,4,5-trimethoxybenzyloxycarbonyl, 2,4,6-trimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 2,4,6-trichlorobenzyloxycarbonyl, 2,4,6-trinitrobenzyloxycarbonyl and the like.
The phenoxycarbonyl group which may have halogen or nitro as a substituent includes, for example, 2-chlorophenoxycarbonyl, 3-chlorophenoxycarbonyl, 4-chlorophenoxycarbonyl, 4-bromophenoxycarbonyl, 4-iodophenoxycarbonyl, 4-fluorophenoxycarbonyl, 2-nitrophenoxycarbonyl, 3-nitrophenoxycarbonyl, 4-nitrophenoxycarbonyl and the like.
The N-lower alkyl-carbamoyl group includes N-(C1-6-alkyl)carbamoyl groups such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl and the like.
The N-(lower alkoxy-carbonyl-lower alkyl)carbamoyl group includes N-[(C1-6-alkoxy)carbonyl(C1-6-alkyl)]carbamoyl groups such as N-(methoxycarbonylmethyl)carbamoyl, N-(ethoxycarbonylmethyl)carbamoyl, N-(propoxycarbonylmethyl)carbamoyl, N-(butoxycarbonylmethyl)carbamoyl, N-(pentyloxycarbonylmethyl)carbamoyl, N-(hexyloxycarbonylmethyl)carbamoyl, N-(2-methoxycarbonylethyl)carbamoyl, N-(3-methoxycarbonylpropyl)carbamoyl, N-(4-methoxycarbonylbutyl)carbamoyl, N-(5-methoxycarbonylpentyl)carbamoyl, N-(6-methoxycarbonylhexyl)carbamoyl and the like.
The N-(carboxy-lower alkyl)carbamoyl group includes N-(carboxy-C1-6-alkyl)carbamoyl groups such as N-(carboxymethyl)carbamoyl, N-(2-carboxyethyl)carbamoyl, N-(3-carboxypropyl)carbamoyl, N-(4-carboxybutyl)carbamoyl, N-(5-carboxypentyl)carbamoyl, N-(6-carboxyhexyl)carbamoyl and the like.
The N-halophenylcarbamoyl group includes N-phenylcarbamoyl groups having on the phenyl ring a halogen atom selected from fluorine, chlorine, bromine and iodine.
Specific examples are N-(2-chlorophenyl)carbamoyl, N-(3-chlorophenyl)carbamoyl, N-(4-chlorophenyl)carbamoyl, N-(2-bromophenyl)carbamoyl, N-(3-bromophenyl)carbamoyl, N-(4-bromophenyl)carbamoyl, N-(2-iodophenyl)carbamoyl, N-(3-iodophenyl)carbamoyl, N-(4-iodophenyl)carbamoyl, N-(2-fluorophenyl)carbamoyl, N-(3-fluorophenyl)carbamoyl, N-(4-fluorophenyl)carbamoyl and the like.
The N-(1-lower alkoxy-carbonyl-2-phenylethyl)carbamoyl group includes N-[1-(C1-6-alkoxy)carbonyl-2-phenylethyl]carbamoyl groups such as N-(1-methoxycarbonyl-2-phenylethyl)carbamoyl, N-(1-ethoxycarbonyl-2-phenylethyl)carbamoyl, N-(1-propoxycarbonyl-2-phenylethyl)carbamoyl, N-(1-butoxycarbonyl-2-phenylethyl)carbamoyl, N-(1-pentyloxycarbonyl-2-phenylethyl)carbamoyl, N-(1-hexyloxycarbonyl-2-phenylethyl)carbamoyl and the like.
The phenyl group which may have halogen as a substituent Includes unsubstituted phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl and the like.
The pyrazolo[1,5-a]pyrimidine derivatives of the present invention have pharmacological effects such as analgesic action, inhibitory effect on nitrogen monoxide synthetase and the like and are useful as analgesics. The derivatives of the invention are also useful as therapeutic or prophylactic agents for septicemia, endotoxin shock, chronic articular rheumatism, etc.
Examples of the derivatives of the invention preferable for medical use include the following (i) and (ii):
(i) compounds of formula (1) wherein R1 is lower alkyl; and
(ii) compounds of formula (1) wherein R1 is phenyl or thienyl, one of R2 and R3 is hydrogen and the other is substituted phenyl having 1 to 3 lower alkoxy groups as substituents and R4 is hydrogen, carboxyl or lower alkoxy-carbonyl.
Among the compounds (i), the following compounds (1a), (1b) and (1c) are more preferred:
(1a) compounds wherein R1 is lower alkyl and R4 is hydrogen, carboxyl or lower alkoxy-carbonyl;
(1b) compounds wherein R1 is lower alkyl and one of R2 and R3 is hydrogen and the other is phenyl having 1 to 3 lower alkoxy groups as substituents, R4 is lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl, phenylthiomethoxycarbonyl, substituted benzyloxycarbonyl having 1 to 3 substituents selected from the group consisting of lower alkoxy, halogen and nitro, phenoxycarbonyl which may have halogen or nitro as a substituent, carbamoyl, N-lower alkyl-carbamoyl, N-benzylcarbamoyl, N-(lower alkoxy-carbonyl-lower alkyl)carbamoyl, N-(carboxy-lower alkyl)carbamoyl, N-halophenylcarbamoyl, N-(1-lower alkoxy-carbonyl-2-phenylethyl)carbamoyl, or the group 
wherein R1, R2 and R3 are as defined in formula (1) and preferably the same as described in this section (1b); and
(1c) compounds wherein R1 is lower alkyl and R2 is hydrogen and R3 and R4 conjointly constitute a group represented by 
wherein the R5s are the same or different and independently represent hydrogen or lower alkoxy.
Of the compounds (1a) to (1c), especially suitable for medical use are those wherein R1 is lower alkyl, more preferably n-butyl.
More preferred of the compounds (ii) are those wherein R1 is phenyl or thienyl, one of R2 and R3 is hydrogen and the other is phenyl having 1 to 3 lower alkoxy groups as substituents and R4 is hydrogen, carboxyl or lower alkoxy-carbonyl.
Other preferable groups of compounds of the invention include a group of compounds (a) wherein R1 is n-butyl, R2 is hydrogen, R3 is naphthyl, pyridyl, phenyl having 1 to 3 lower alkoxy groups as substituents or halogen-substituted phenyl and R4 is hydrogen or lower alkylthio; and a group of compounds (b) wherein R1 is n-propyl or n-butyl, R2 is substituted phenyl having 1 to 3 substituents selected from the group consisting of lower alkoxy, phenyl-lower alkoxy and hydroxyl, or phenyl which may have a substituent selected from the group consisting of N,N-di-lower alkylamino, halogen-substituted lower alkyl and halogen, R3 is hydrogen and R4 is carboxyl, lower alkoxy-carbonyl, phenylthiomethoxycarbonyl, substituted benzyloxycarbonyl having 1 to 3 substituents selected from the group consisting of lower alkoxy, halogen and nitro, phenoxycarbonyl which may have halogen or nitro as a substituent, or the group 
wherein R1, R2 and R3 are as defined above in formula (1) and preferably the same as shown in this section (b).
Most preferable compounds of the invention for medical use include compounds wherein R1 is n-butyl, R2 is hydrogen, R3 is pyridyl, more preferably 2-pyridyl and R4 is hydrogen, and compounds wherein R1 is n-butyl, R2 is phenyl having 3 lower alkoxy groups as substituents or phenyl having 2 lower alkoxy groups and 1 hydroxyl group as substituents, more preferably 3,4,5-trimethoxyphenyl, R3 is hydrogen and R4 is carboxyl.
Methods for producing the derivatives of the invention are described below in detail.
The derivatives of the present invention can be produced, for example, by processes shown below in Reaction Scheme-1 to Reaction Scheme-10. 
wherein R1, R2 and R3 are as defined above, X represents halogen, Q and Z independently represent lower alkyl, "psgr" is naphthyl, furyl, pyridyl, styryl, phenylethynyl, substituted phenyl having 1 to 3 substituents selected from the group consisting of lower alkoxy, phenyl-lower alkoxy and hydroxyl, or phenyl which may have a substituent selected from the group consisting of lower alkylthio, N,N-di-lower alkylamino, halogen-substituted lower alkyl, phenyl, nitro, methylenedioxy and halogen.
The halogen atom represented by X includes fluorine, chlorine, bromine and iodine.
According to Reaction Scheme-1, a known compound (2) is reacted with a known compound (3) to produce a compound (4). The compound (4) is converted to a compound (5), which is then reacted with a known compound (6) to produce a compound (1a) of the present invention.
The reaction between the compound (2) and compound (3) can be carried out in the presence of a base in a suitable inert solvent at temperatures in the range of 0xc2x0 C. to room temperature. Examples of inert solvents include N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), tetrahydrofuran (THF), dimethoxyethane (DME), benzene, toluene and the like. Examples of bases include sodium hydride, potassium hydride, sodium ethoxide, potassium-t-butoxide and the like. Each of the compound (3) and the base is usually used in an equimolar amount to an about 5-fold molar amount, relative to the compound (2). The reaction is completed in about 2 to about 100 hours.
The compound (4) thus obtained is treated with an aqueous alkali solution such as an aqueous sodium hydroxide solution, aqueous potassium hydroxide solution or the like at temperatures in the range of room temperature to about 100xc2x0 C. for about 30 minutes to about 5 hours, thus converting to the compound (5). Since the aqueous alkali solution functions as a solvent in the above treatment reaction, it is unnecessary to use other solvents. However, other inert solvents such as methanol, ethanol and the like may be used.
The compound (5) resulting from the above reaction is reacted with an aldehyde derivative (6) to convert to a compound (1a) of the present invention. The reaction can be carried out using an aqueous alkali solution such as aqueous sodium hydroxide solution, aqueous potassium hydroxide solution or the like in an inert solvent such as methanol, ethanol or the like at temperatures in the range of about xe2x88x9210xc2x0 C. to room temperature for about 10 minutes to about 3 hours. Each of the aldehyde derivative (6) and the aqueous alkali solution is used in an equivalent amount to a slight excess, relative to the compound (5).
The reactions for converting the compound (4) to the compound (5) and synthesizing the compound (1a) therefrom shown in Reaction Scheme-1 may be sequentially carried out in the same reactor. 
wherein R1, Q, X and "psgr" are as defined above, R2a is naphthyl, furyl, pyridyl, styryl, phenylethynyl, substituted phenyl having 1 to 3 substituents selected from the group consisting of lower alkoxy, phenyl-lower alkoxy and hydroxyl, or phenyl which may have a substituent selected from the group consisting of lower alkylthio, N,N-di-lower alkylamino, halogen-substituted lower alkyl, phenyl, nitro, methylenedioxy and halogen.
In Reaction Scheme-2, the compound (2) is reacted with a known compound (7) in an inert solvent such as DMF, DMA, THF, DME, benzene, toluene or the like in the presence of a base such as sodium hydride, potassium hydride, sodium ethoxide or the like at 0xc2x0 C. to about reflux temperature of the solvent. Each of the compound (7) and the base is usually used in an equimolar amount to an about 5-fold molar amount, relative to the compound (2). The reaction is completed in about 1 to about 50 hours.
Subsequently, the diester derivative (8) thus obtained is heated in an inert solvent such as water, water-DMF or the like at about reflux temperature of the solvent for about 3 to about 50 hours, thus converting to a monoester derivative (9).
The reactions for converting the compound (2) to the compound (8) and synthesizing the compound (9) therefrom shown in Reaction Scheme-2 may be sequentially carried out in the same reactor.
The compound (9) resulting from the above reaction is reacted with a known aldehyde derivative (6) using an alkali such as lithium diisopropylamide, lithium dibutyl amide or the like in an inert solvent such as THF, 1,4-dioxane or the like at temperatures in the range of about xe2x88x92100xc2x0 C. to room temperature for about 5 to about 100 hours. Each of the aldehyde derivative (6) and the alkali is used in an equivalent amount to a slight excess, relative to the compound (5). 
wherein R1, R2, R3, X, Z and "psgr" are as defined above, R4a is hydrogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy-carbonyl, lower alkyl, phenylthiomethoxycarbonyl, substituted benzyloxycarbonyl having 1 to 3 substituents selected from the group consisting of lower alkoxy, halogen and nitro, phenoxycarbonyl which may have halogen or nitro as a substituent, or phenyl which may have halogen as a substituent.
In Reaction Scheme-3, the compound (2) is reacted with a known compound (10) in an inert solvent such as THF, 1,4-dioxane, diethyl ether, DMF or the like in the presence of a base such as n-butyl lithium, n-hexyl lithium, sodium hydride or the like at temperatures in the range of about xe2x88x92100xc2x0 C. to room temperature. Each of the compound (10) and the base is usually used in about a slight excess molar to an about 5-fold molar amount, relative to the compound (2). The reaction is completed in about 10 minutes to about 3 hours.
Subsequently, the compound (11) thus obtained is reacted with a known aldehyde derivative (6) to convert to a compound (1d) of the present invention. This reaction can be carried out using an alkali such as sodium hydride, potassium hydride, sodium ethoxide or potassium-t-butoxide in an inert solvent such as dimethoxyethane, diethylene glycol dimethyl ether, t-butanol, THF or the like at room temperature to about reflux temperature of the solvent for about 1 to about 150 hours. Each of the aldehyde derivative (6) and the alkali is used in an equivalent amount to a slight excess, relative to the compound (11). 
wherein R1, R2, R3 and "psgr" are as defined above and R4b is hydrogen or lower alkyl.
In Reaction Scheme-4, the compound (2) is reacted with a known ketone compound (12) in the presence of an alkali such as lithium diisopropylamide, lithium dibutyl amide or the like in an inert solvent such as THF, 1,4-dioxane or the like at temperatures in the range of about xe2x88x92100xc2x0 C. to room temperature for about 5 to about 100 hours. Each of the ketone derivative (12) and the alkali is used in a slight molar excess to an about 5-fold molar amount, relative to the compound (2). If necessary, hexamethylphosphoric triamide may be added to the reaction system in a slight molar excess to an about 5-fold molar amount, relative to the compound (2).
Subsequently, the compound (13) thus obtained is subjected to a reduction reaction in a lower alcohol inert solvent such as methanol, ethanol or the like using a boron hydride compound such as sodium borohydride, or in an inert solvent such as diethyl ether, THF or the like using an aluminum hydride compound such as lithium aluminum hydride. Each of the boron hydride compound and the aluminum hydride compound is used in an amount of about 1 to about 6 equivalents, calculated as hydrides. The reaction is completed at temperatures in the range of about 0xc2x0 C. to room temperature in about 10 minutes to about 3 hours.
Subsequently, the alcohol derivative (14) thus obtained is converted to a compound (1e) of the present invention, for example, by either of the following two methods.
(1) Dehydration Reaction With an Acid Catalyst
The compound (14) is treated in the presence of an acid catalyst such as p-toluenesulfonic acid, sulfuric acid or the like in an inert solvent such as benzene, toluene, xylene or the like at temperatures in the range of room temperature to about reflux temperature of the solvent for about 1 to about 10 hours. If necessary, an excess of an anhydrous inorganic salt such as anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or the like may be added to the reaction system.
(2) Dehydrohalogenation Reaction After Halogenation
The compound (14) is treated with an equivalent amount to a slight equivalent excess of a halogenating agent such as thionyl chloride, thionyl bromide, phosphorus oxychloride or the like in an inert solvent such as dichloromethane, 1,2-dichloroethane, diethyl ether or the like. An equivalent amount to a slight excess of a tertiary amine such as pyridine, lutidine, collidine, triethylamine or the like may be added to the reaction system. The treatment reaction is carried out at temperatures in the range of 0xc2x0 C. to room temperature for about 5 minutes to about 2 hours.
Subsequently, the compound thus obtained is dehydrohalogenated. The reaction can be carried out in an inert solvent such as benzene, toluene, xylene or the like using about an equimolar amount to an about 3-fold molar amount of a deacidification agent such as 1,8-diazabicyclo[5,4-0]-7-undecene (DBU), triethylamine, N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine or the like, relative to the starting compound. The reaction is usually carried out at temperatures in the range of 0xc2x0 C. to room temperature and is completed in about 10 minutes to about 2 hours. 
wherein R1, R2, R2a, R3 and Q are as defined above.
In Reaction Scheme-5, the compound (1f) is hydrolyzed in an inert solvent such as methanol, ethanol or the like using an aqueous alkali solution such as aqueous sodium hydroxide solution, aqueous potassium hydroxide solution or the like. The aqueous alkali solution is used in an equivalent amount to a slight excess, relative to the compound (1f). The reaction is carried out at temperatures in the range of 0xc2x0 C. to room temperature and is completed in about 0.5 to about 10 hours. 
wherein R1, R2, R2a, R3 and Q are as defined above.
In Reaction Scheme-6, the compound (1c) is decarboxylated by heating the compound (1c) in an inert solvent such as benzene, toluene, xylene or the like in the presence of an amine such as DBU, triethylamine, N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine or the like, and a thiol such as thiophenol, ethanethiol or the like at about reflux temperature of the solvent for about 30 minutes to about 5 hours. Both of the amine and thiol are used in a catalytic amount. 
wherein R1, R2 and R3 are as defined above, xcexa9 is lower alkyl, phenylthiomethyl, substituted benzyl having 1 to 3 substituents selected from the group consisting of lower alkoxy, halogen and nitro, or phenyl which may have halogen or nitro as a substituent.
In the above definition, the substituted benzyl having 1 to 3 substituents selected from the group consisting of lower alkoxy, halogen and nitro includes, for example, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3-ethoxybenzyl, 3-propoxybenzyl, 3-butoxybenzyl, 3-pentyloxybenzyl, 3-hexyloxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-iodobenzyl, 4-fluorobenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl, 2,4-dinitrobenzyl, 3,5-dinitrobenzyl, 2,3,4-trimethoxybenzyl, 2,3,5-trimethoxybenzyl, 2,3,6-trimethoxybenzyl, 2,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2,4,6-trichlorobenzyl, 2,4,6-trinitrobenzyl and the like.
The phenyl which may have halogen or nitro as a substituent includes 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-fluorophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl and the like.
The conversion reaction of the compound (1h) to compound (1i) shown in Reaction Scheme-7 is carried out, for example, by either of the following two methods.
(1) Reaction With a Halide
The compound (1h) is reacted with a halide of the formula xcexa9-X (wherein xcexa9 and X are as defined above) in an inert solvent such as DMF, DMA, THF, dichloromethane or the like in the presence of a deacidification agent such as triethylamine, N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine or the like. Each of the halide and the deacidification agent is used in about an equimolar amount to an about 3-fold molar amount, relative to the compound (1h). The reaction is usually carried out at room temperature to reflux temperature of the solvent for about 30 minutes to about 5 hours.
(2) Reaction With an Oxy Derivative
The compound (1h) is reacted with an oxy derivative of the formula xcexa9-OH (wherein xcexa9 is as defined above) in an inert solvent such as dichloromethane, 1,2-dichloroethane or the like in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC), diethoxy phosphoryl cyanide (DEPC) or the like. Each of the oxy derivative and the dehydrating agent is used in an equivalent amount to a slight equivalent excess, relative to the compound (1h). The reaction is usually carried out at 0xc2x0 C. to room temperature and is completed in about 5 hours to about 100 hours. 
wherein R1, R2 and R3 are as defined above, xcexa3 is hydrogen, lower alkyl, benzyl, lower alkoxy-carbonyl-lower alkyl, halophenyl or 1-lower alkoxy-carbonyl-2-phenylethyl.
The lower alkoxy-carbonyl-lower alkyl group represented by xcexa3 includes (C1-6-alkoxy)carbonyl-(C1-6-alkyl) groups. The halophenyl group includes a phenyl group having on the phenyl ring, a halogen atom selected from fluorine, chlorine, bromine and iodine. The 1-lower alkoxy-carbonyl-2-phenylethyl group includes 1-(C1-6-alkoxy)carbonyl-2-phenylethyl.
The conversion reaction of the compound (1h) to a compound (1j) shown in Reaction Scheme-8 is carried out by the following method. The compound (1h) is reacted with a chloroformic acid ester such as isobutyl chloroformate, methyl chloroformate or the like in an inert solvent such as THF, diethyl ether, 1,4-dioxane or the like in the presence of a tertiary amine such as triethylamine, trimethylamine, N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine or the like to produce a mixed acid anhydride. The mixed acid anhydride is reacted with an amine derivative represented by the formula xcexa3-NH2 wherein xcexa3 is as defined above. Each of the composition for elimination, tertiary amine and amine derivative is used in an equivalent amount to a slight equivalent excess, relative to the compound (1h). The reaction treatment with the compound for elimination is usually carried out at temperatures in the range of 0xc2x0 C. to room temperature for about 10 minutes to about 1 hour. The reaction treatment with the amine derivative is usually carried out at temperatures in the range of 0xc2x0 C. to room temperature for about 30 minutes to about 10 hours. The reactions may be sequentially carried out in the same reactor.
The conversion reaction of the compound (1h) to the compound (1j) shown in Reaction Scheme-8 may also be carried out in accordance with the method (2) of Reaction Scheme-7 (Reaction with an oxy derivative), which comprises reacting the compound (1h) with an amine derivative of xcexa3-NH2 (wherein xcexa3 is as defined above) in the presence of a dehydrating agent. The amounts of the amine derivative and the dehydrating agent and the reaction conditions may be the same as in the method (2) of Reaction Scheme-7. 
wherein R1 is lower alkyl, thienyl or phenyl; one of R2b and R3a is hydrogen and the other is naphthyl, substituted phenyl having 1 to 3 substituents selected from the group consisting of lower alkoxy, phenyl-lower alkoxy and hydroxyl, or phenyl which may have a substituent selected from the group consisting of N,N-di-lower alkylamino, halogen-substituted lower alkyl, phenyl, nitro, methylenedioxy and halogen.
The oxidation reaction of the compound (1k) shown in Reaction Scheme-9 can be carried out using an oxidizing agent such as hydrogen peroxide, m-chloroperbenzoic acid, sodium periodate or the like in an inert solvent such as acetic acid, dichloromethane, carbon tetrachloride or the like. Using the oxidizing agent in an equivalent amount to a slight equivalent excess relative to the starting compound, a sulfinyl compound (n=1) is obtained by the oxidation reaction at 0xc2x0 C. to room temperature for about 15 minutes to about 10 hours. To obtain a sulfonyl compound (n=2), the oxidizing agent is used in an amount of 2 equivalents or more relative to the starting compound, optionally using a catalyst such as sodium tungstate or the like, and the reaction is carried out at temperatures in the range of 0xc2x0 C. to reflux temperature of the solvent for about 15 minutes to about 10 hours.
The desired compound wherein n=2 (sulfonyl compound) can also be produced by oxidizing the compound wherein n=1 (sulfinyl compound) once again in a similar manner. The reaction can be carried out under any of the above-mentioned conditions. 
wherein R1, R5, Q and Z are as defined above.
The reaction between the compound (4) and known salicylaldehyde derivative (15) shown in Reaction Scheme-10 can be carried out in a similar manner as in the reaction between the compound (11) and aldehyde derivative (6) shown in Reaction Scheme-3. The solvent and reaction conditions may also be the same as in the reaction between the compound (11) and aldehyde derivative (6). If necessary, an equivalent amount to a slight excess of a crown ether such as 18-crown-6 may be used in the reaction. 
wherein R1, R2 and R3 are as defined above, R4c is N-(lower alkoxy-carbonyl-lower alkyl)carbamoyl or N-(1-lower alkoxy-carbonyl-2-phenylethyl)carbamoyl, and R4d is N-(carboxy-lower alkyl)carbamoyl or N-(1-carboxy-2-phenylethyl)carbamoyl.
According to Reaction Scheme-11, the compound (1n) obtainable by the method shown in Reaction Scheme-8 is hydrolyzed to form a compound (1p). The hydrolysis of the compound (1n) can be carried out in a similar manner as in the hydrolysis of the compound (1f) shown in Reaction Scheme-5, thus giving the compound (1p) having a corresponding hydrolyzed group. 
wherein R1 and R4 are as defined above, one of R2c and R3c is hydrogen and the other is substituted phenyl having 1 to 3 benzyloxy groups and optionally further having 1 to 2 lower alkoxy groups, R2d and R3d correspond to R2c and R3c and one of R2d and R3d is a substituted phenyl group having hydroxyl groups in place of benzyloxy groups (i.e., substituted phenyl having 1 to 3 hydroxyl groups and optionally further having 1 to 2 lower alkoxy groups).
As shown in Reaction Scheme-12, the compound (1q) having benzyloxy-substituted phenyl is hydrogenolized to convert benzyloxy groups into hydroxyl groups. The reaction can be carried out in an inert solvent such as ethanol, methanol, ethyl acetate or the like in the presence of a catalytic amount of a catalyst such as palladium-carbon, platinum oxide, Raney nickel or the like in an atmosphere of hydrogen in a stoichiometric amount or more at temperatures in the range of 0xc2x0 C. to room temperature. The reaction is completed in about 5 minutes to about 1 hour, thus giving a compound (1r).
In the above reaction, it is preferable to promptly stop the reaction upon consumption of a stoichiometric amount of hydrogen so that double bonds of carbon atoms bound to R2c and R3c of the starting compound may not be hydrogenated.
The compounds obtained by the processes shown in the above Reaction Schemes can be easily isolated by conventional separation and purification methods. Examples of such methods include adsorption chromatography, preparative thin-layer chromatography, recrystallization, solvent extraction and the like.
The compounds of the invention can be formed into pharmaceutically acceptable acid addition salts. The compounds of the invention include such salts. Acids for use to form such acid addition salts are, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like and organic acids such as oxalic acid, fumaric acid, maleic acid, tartaric acid, citric acid, p-toluenesulfonic acid and the like. These acid addition salts can be formed according to conventional methods.
The compounds of the invention can be formed into alkali metal salts such as sodium salts, potassium salts or the like, alkaline earth metal salts such as calcium salts, magnesium salts or the like and other salts such as copper salts or the like, by conventional methods. Such salts also constitute part of the compounds of the invention.
Some of the compounds of the invention exist as optical isomers having a carbon atom as an asymmetric center. Optical isomers in the form of R-body, S-body and racemic body are included among the compounds of the invention.
For use, the compounds of the invention are usually shaped into general dosage forms for pharmaceutical compositions with pharmaceutically acceptable carriers. Examples of pharmaceutically acceptable carriers include conventional diluents or excipients such as fillers, volume builders, binders, humectants, disintegrators, surfactants, lubricants and the like. These carriers are selectively used according to the desired unit dosage form.
The unit dosage form for the pharmaceutical compositions of the invention can be selected from a broad variety of forms according to the intended medical treatment. Typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), ointments, and the like.
For preparing tablets by molding, usable as the above pharmaceutically acceptable carriers are excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and potassium phosphate; binders such as water, ethanol, propanol, simple syrup, glucose syrup, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose and polyvinyl pyrrolidone; disintegrators such as sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen-carbonate and calcium carbonate; surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate and stearyl monoglyceride; disintegration inhibitors such as sucrose, stearin, cacao butter and hydrogenated oil; absorption promoters such as quaternary ammonium base and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; and lubricants such as purified talc, stearic acid salt, boric acid powder and polyethylene glycol.
The tablets may further be made into coated tablets such as sugar-coated tablets, gelatin-coated tablets, enteric tablets, film-coated tablets, double-layered tablets or multiple-layered tablets.
For preparing pills by molding, usable as pharmaceutically acceptable carriers are excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; and disintegrators such as laminaran and agar.
For formulating suppositories, usable as pharmaceutically acceptable carriers are polyethylene glycol, cacao butter, a higher alcohol or its esters, gelatin, semisynthetic glycerides and the like. The capsules are usually manufactured in a conventional manner by blending the compound of the invention with one or more pharmaceutically acceptable carriers as exemplified above and encapsulating the mixture into hard gelatin capsule shells, soft capsule shells, etc.
When the pharmaceutical preparation is to be provided in an injectable form such as a solution, an emulsion or a suspension, the preparation is preferably sterilized and rendered isotonic to the blood. Diluents for use in such preparation are, for example, water, ethanol, macrogols, propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like. In this case, sodium chloride, glucose or glycerin may be added to the pharmaceutical composition in an amount sufficient to provide an isotonic solution. Conventional solubilizers, buffers, anesthetics and the like may also be added to the pharmaceutical composition.
Further, if desired, coloring agents, preservatives, aromatics, flavors, sweeteners or other medicines may be incorporated into the pharmaceutical composition.
For preparing ointments in the form of pastes, creams, gels, etc., usable as diluents are white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like.
The present inventors found that when a pyrazolo[1,5-a]pyrimidine derivative of formula (1) wherein R4 is carboxyl is used as an active ingredient and mixed with a suitable acid polymer, oral administration of the resulting mixture (composition) improves permeability of the active ingredient through the intestinal membrane. Examples of useful acid polymers are aqueous solutions and suspensions of acid polymers at or below pH 6. Specific examples include hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, methacrylic acid/methacrylate copolymers and the like. Particularly preferred are methacrylic acid/methacrylate copolymers (1:1) (e.g., trade name: Eudragit L100, product of Rohm Pharm. Co., Ltd.)
The proportion of the compound of the formula (1) of the invention (active ingredient) in the pharmaceutical preparation is not critical and can be selected from a broad range. It is usually preferable for the compound to account for about 1 to about 70 wt. % of the pharmaceutical preparation.
There is no limitation on the method for administering the pharmaceutical preparation. A proper method can be selected according to the dosage form, patient""s age, sex and other conditions, severity of disease, etc. For example, the tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered by the oral route. The injections are administered singly or in admixture with glucose, amino acid or like conventional infusions by the intravenous route or if necessary, administered singly by the intramuscular, intradermal, subcutaneous or intraperitoneal route. The suppositories are administered intrarectally.
The dosage of the pharmaceutical preparation is suitably selected according to the intended use, patient""s age, sex and other conditions, severity of disease, etc. The dosage of the compound of the invention as the active ingredient is preferably about 0.5 to about 20 mg per kg body weight a day for human adult. The pharmaceutical preparation may be administered once a day or in 2-4 divided doses a day.